WO95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or N+Oxe2x88x92, and the remaining a, b, c and d groups represent CR1 or CR2; or
each of a, b, c, and d are independently selected from CR1 or CR2;
X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present;
the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent xe2x80x94R15, halo, xe2x80x94OR16, xe2x80x94OCO2R16 or xe2x80x94OC(O)R15, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR16)2, H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R15, H and xe2x80x94OR15, xe2x95x90O, aryl and H, xe2x95x90NOR15 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein p is 2, 3 or 4;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR15 (e.g., xe2x80x94OCH3), xe2x80x94COR15, xe2x80x94SR15 (e.g., xe2x80x94SCH3 and xe2x80x94SCH2C6H5), xe2x80x94S(O)tR16 (wherein t is 0, 1 or 2, e.g., xe2x80x94SOCH3 and xe2x80x94SO2CH3), xe2x80x94N(R15)2, xe2x80x94NO2, xe2x80x94OC(O)R15, xe2x80x94CO2R15, xe2x80x94OCO2R16, xe2x80x94CN, xe2x80x94NR15COOR16, xe2x80x94SR16C(O)OR16 (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR16N(R17)2 (provided that R16 in xe2x80x94SR16N(R17)2 is not xe2x80x94CH2xe2x80x94) wherein each R17 is independently selected from H or xe2x80x94C(O)OR16 (e.g., xe2x80x94S(CH2)2NHC(O)O-t-butyl and xe2x80x94S(CH2)2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR15 or xe2x80x94CO2R15;
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, and R7 each independently represents H, xe2x80x94CF3, xe2x80x94COR15, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR15, xe2x80x94SR15, xe2x80x94S(O)tR16, xe2x80x94NR15COOR16, xe2x80x94N(R15)2, xe2x80x94NO2, xe2x80x94COR15, xe2x80x94OCOR15, xe2x80x94OCO2R16, xe2x80x94CO2R15, OPO3R15, or R5 is combined with R6 to represent xe2x95x90O or xe2x95x90S;
R8 is selected from: H, C3 to C4 alkyl (preferably branched chain alkyl, and most preferably C4 to C7 branched chain alkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl;
the substituents for the R8 substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, xe2x80x94N(R18)2, xe2x80x94OR18, cycloalkyalkyl, halo, CN, xe2x80x94C(O)N(R18)2, xe2x80x94SO2N(R18)2 or xe2x80x94CO2R18; provided that the xe2x80x94OR18 and xe2x80x94N(R18)2 substituents are not bound to the carbon that is bound to the N of the xe2x80x94C(O)NR8-moiety;
each R18 is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;
R9 and R10 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or xe2x80x94CON(R18)2 (wherein R18 is as defined above); and the substitutable R9 and R10 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl (i.e., the R9 and/or R10 groups can be unsubstituted or can be substituted with 1-3 of the substituents described above, except when R9 and/or R10 is H); or
R9 and R10 together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring;
R11 and R12 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, xe2x80x94CON(R18)2 xe2x80x94OR18 or xe2x80x94N(R18)2; wherein R18 is as defined above; provided that the xe2x80x94OR18 and xe2x80x94N(R18)2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R11 and R12 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or
R11 and R12 together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring;
R13 is an imidazolyl ring selected from: 
wherein R19 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (7) xe2x80x94C(aryl)3 (e.g., xe2x80x94C(phenyl)3, i.e., trityl) or (8) cycloalkyl;
said imidazolyl ring 2.0 or 2.1 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional substituents are independently selected from: xe2x80x94NHC(O)R18, xe2x80x94C(R34)2OR35, xe2x80x94OR18, xe2x80x94SR18, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or xe2x80x94N(R18)2 (wherein each R18 is independently selected); R18 is as defined above; each R34 is independently selected from H or alkyl (preferably xe2x80x94CH3), preferably H; R35 is selected from H, xe2x80x94C(O)OR20, or xe2x80x94C(O)NHR20, and R20 is as defined below (preferably R20 is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (e.g., phenyl), a cycloalkyl ring (e.g., cyclopentyl or cyclohexyl) or a heteroaryl ring (e.g., furanyl, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q is optionally substituted with 1 to 4 substituents independently selected from halo (e.g., F or Cl), alkyl, aryl, xe2x80x94OR18, xe2x80x94N(R18)2 (wherein each R18 is independently selected), xe2x80x94OC(O)R18, or xe2x80x94C(O)N(R18)2 (wherein each R18 is independently selected), and wherein R18 is as defined above: (examples of the xe2x80x94C(R34)2OR35 group include xe2x80x94CH2OH, xe2x80x94CH2OC(O)OR20 and xe2x80x94CH2OC(O)NHR20);
R14 is selected from: 
R15 is selected from: H, alkyl, aryl or arylalkyl;
R16 is selected from: alkyl or aryl;
R20 is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R20 is not H when R14 is group 5.0 or 8.0;
when R20 is other than H, then said R20 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, xe2x80x94OC(O)R18 (e.g., xe2x80x94OC(O)CH3), xe2x80x94OR18 or xe2x80x94N(R18)2, wherein each R18 group is the same or different, and wherein R18 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;
when R21 is other than H, then said R21 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, xe2x80x94OR18 or xe2x80x94N(R18)2, wherein each R18 group is the same or different, and wherein R18 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
n is 0-5;
each R32 and R33 for each n (i.e., for each xe2x80x94C(R32)(R33)xe2x80x94 group), are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, xe2x80x94CON(R18)2, xe2x80x94OR18 or xe2x80x94N(R18)2; wherein R18 is as defined above; and wherein said substitutable R32 and R33 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or
R32 and R33 together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring; and
R36 is selected from branched alkyl, unbranched alkyl cycloalkyl, heterocycloalkyl, or aryl (e.g., phenyl); and
provided that:
(1) when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R8 is selected from: C3 to C10 alkyl, substituted C3 to C10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; and
(2) when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cycloalkyl ring.
This invention also provides compounds of formula 1.0, as described above, wherein when R14 is group 5.0, and X is N, and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cyloalkyl ring.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor: (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells. DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following terms are used as defined below unless otherwise indicated:
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
BOC-represents tert-butyloxycarbonyl;
CBZ-represents xe2x80x94C(O)OCH2C6H5 (i.e., benzyloxycarbonyl);
CH2Cl2-represents dichloromethane;
CIMS-represents chemical ionization mass spectrum;
DEAD-represents diethylazodicarboxylate;
DEC-represents EDCI which represents 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride;
DMF-represents N,N-dimethylformamide;
Et-represents ethyl;
EtOAc-represents ethyl acetate;
EtOH-represents ethanol;
HOBT-represents 1-hydroxybenzotriazole hydrate;
IPA-represents isopropanol;
iPrOH-represents isopropanol;
Me-represents methyl;
MeOH-represents methanol;
MS-represents mass spectroscopy;
NMM-represents N-methylmorpholine;
Ph-represents phenyl;
Pr-represents propyl;
TBDMS-represents tert-butyldimethylsilyl;
TEA-represents triethylamine;
TFA-represents trifluoroacetic acid;
THF-represents tetrahydrofuran;
Tr-represents trityl;
alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
acyl-represents a Gxe2x80x94C(O)xe2x80x94 group wherein G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, xe2x80x94O-alkyl, xe2x80x94O-aryl, or NR25R26 wherein R25 and R26 are independently selected from alkyl or aryl;
arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
aryl-(including the aryl portion of arylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, xe2x80x94C(O)N(R18)2, xe2x80x94SO2R18, xe2x80x94SO2N(R18)2, amino, alkylamino, dialkylamino, xe2x80x94COOR23 or xe2x80x94NO2, wherein R23 represents alkyl or aryl; and
cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring being optionally substituted with one or more (e.g., 1, 2 or 3) alkyl groups (e.g., methyl or ethyl) and when there is more than one alkyl group each alkyl group is independently selected;
cycloalkylalkyl-represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined above, such that the bond from another substituent is to the alkyl moiety;
halo-represents fluoro, chloro, bromo and iodo;
heteroaralkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety;
heteroaryl-represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-[1,2,4-triazinyl], 3- or 5-[1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 
heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR24, wherein R24 represents alkyl, aryl, xe2x80x94C(O)N(R18)2 wherein R18 is as above defined (e.g., xe2x80x94C(O)NH2) or acyl-(suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, etc.).
The positions in the tricyclic ring system are: 
The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): 
Examples of R8 substituents include: benzyl, xe2x80x94CH2C(CH3)2, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopropyl, xe2x80x94(CH2)2CH3, 
Examples of R9 and R10 groups include H and benzyl
Examples of R11 and R12 groups include: H, xe2x80x94CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94(CH2)3CH3, benzyl, ethyl, p-chlorophenyl, and xe2x80x94OH.
Cyclopropyl is an Example of the R11 and R12 group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring.
Examples of the optional substituents for the R13 moiety include: xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2OC(O)O-cyclohexyl, xe2x80x94CH2OC(O)O-cyclopentyl, ethyl, isopropyl, NH2, and xe2x80x94NHC(O)CF3.
Examples of R19 include: xe2x80x94C(O)NH-cyclohexyl, xe2x80x94C(phenyl)3, H, methyl or ethyl.
Examples of R20 for group 5.0 include: t-butyl, ethyl, benzyl, xe2x80x94CH(CH3)2, xe2x80x94CH2CH(CH3)2, xe2x80x94(CH2)2CH3, n-butyl, n-hexyl, n-octyl, p-chlorophenyl, cyclohexyl, cyclopentyl, 
Another example of R20 for group 5.0 is 
Examples of R20 and R21 for 6.0 include: cyclohexyl, t-butyl, H, xe2x80x94CH(CH3)2, ethyl, xe2x80x94(CH2)2CH3, phenyl, benzyl, xe2x80x94(CH2)2phenyl, and xe2x80x94CH3.
Examples of R20 for 7.0 include: 4-pyridylNO, xe2x80x94OCH3, xe2x80x94CH(CH3)2, -t-butyl, H, propyl, cyclohexyl and 
Examples for R36 for 7.1 include: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 
Examples for R20 for 8.0 include: methyl, i-propyl and cyclohexylmethyl.
Examples of R32 and R33 include: H, phenyl, xe2x80x94OH and benzyl.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R8 is selected from: C3 to C10 alkyl, substituted C3 to C10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cyloalkyl ring.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is group 5.0, and X is C or CH (preferably CH), and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cyloalkyl ring.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0. 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is 5.0 and X is C or CH (preferably CH), then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
Compounds of this invention include compounds of formula 1.0 wherein when R14 is 5.0 and X is N, then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
Thus, one embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0 and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is N and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is N, R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is N, R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is N, R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein when R14 is group 5.0, and X is C or CH (preferably CH), and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein when R14 is group 5.0, and X is N, and R8 is H, then the alkyl chain between R13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the xe2x80x94C(O)NR18 group) is substituted, i.e.,: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and/or (b) R9 and R10, and/or R11 and R12, are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably, heteroarylalkyl) and the other substituents are as defined for formula 1.0.
Another embodiment of this invention is directed to compounds wherein R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.
R1, R2, R3, and R4 are preferably selected from H or halo, and are more preferably selected from H, Br, F, or Cl, and are most preferably selected from H, Br or Cl. Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (1) 3,8,10-trihalo; (2) 3,7,8-trihalo; (3) 3,8-dihalo; (4) 8-halo; and (5) 10-halo substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: (1) 3-Br,8xe2x80x94Cl,10-Br-substituted compounds; (2) 3-Br,7-Br,8-Cl-substituted compounds; (3) 3-Br,8-Cl-substituted compounds; (4) 8-Cl-substituted compounds; and (5) 10-Cl-substituted compounds. The 3,8-dihalo compounds are more preferred and the 8-halo compounds are most preferred. Thus, for example, 3-Br,8-Cl substituted compounds are more preferred and 8-Cl substituted compounds are most preferred.
Substituent a is preferably N or N+Oxe2x88x92 with N being preferred.
A and B are preferably H2, i.e., the optional bond is absent and the C5-C6 bridge is unsubstituted.
R5, R6, and R7 are preferably H.
X is preferably N or CH (i.e., the optional bond is absent), and more preferably X is N.
R8 is preferably selected from: arylalkyl, substituted aryl alkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. Most preferably, R8 is selected from: aryl-(C1-C4)alkyl, substituted aryl-(C1-C4)alkyl, heteroaryl-(C1-C4)alkyl, substituted heteroaryl-(C1-C4)alkyl, cycloalkyl-(C1-C4)alkyl, or substituted cycloalkyl-(C1-C4)alkyl. More preferably, R8 is selected from: aryl-CH2-, substituted aryl-CH2-, heteroaryl-CH2-, substituted heteroaryl-CH2, cycloalkyl-CH2- or substituted cycloalkyl-CH2-. Even more preferably, R8 is selected from: benzyl, 3-pyridylmethyl, 4-fluoro-benzyl or cyclopropylmethyl, and still more preferably R8 is benzyl.
R13 is preferably ring 2.0 or 4.0. When substituted on the substitutable carbon atoms of the imidazole ring, the substituents are generally selected from: xe2x80x94N(R18)2, xe2x80x94NHC(O)R18, xe2x80x94C(R34)2OR35, or alkyl, e.g., xe2x80x94CH3, xe2x80x94CH2OH, xe2x80x94CH2OC(O)O-cyclohexyl, xe2x80x94CH2OC(O)O-cyclopentyl, ethyl, isopropyl, NH2, or xe2x80x94NHC(O)CF3.
R19 is preferably H or alkyl, most preferably H, methyl or ethyl, and more preferably methyl.
R14 is preferably a carbamate group represented by substituent 5.0 described above. Preferably, R20 for substituent 5.0 is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with xe2x80x94OH provided that said xe2x80x94OH substituent is not bound to a carbon that is adjacent to an oxygen atom. More preferably R20 for substituent 5.0 is selected from: C1 to C4 alkyl and C5 to C7 cycloalkyl. Most preferably R20 for substituent 5.0 is selected from: t-butyl, i-propyl and cyclohexyl, with i-propyl and cyclohexyl being more preferred, and with cyclohexyl being even more preferred.
R20 in substituent 6.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl; and more preferably cyclohexyl. R21 is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably H.
R20 in substituent 7.0 is preferably selected from: cycloalkyl or alkyl; most preferably cyclohexyl, cyclopentyl, isopropyl; and more preferably cyclohexyl.
R36 in substituent 7.1 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 
and most preferably selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
R20 in substituent 8.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.
R9, R10, R11, and R12 are preferably selected from: H, C1 to C4 alkyl (e.g., methyl or isopropyl), xe2x80x94CON(R18)2 (e.g., xe2x80x94CONH2), or when R9 and R10, and/or R11 and R12 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl.
R9, R10, R11, and R12 are preferably H when R14 is the carbamate substituent 5.0 and R8 is not H.
When R14 is selected from substituents 6.0, 7.0, 7.1 and 8.0, and at least one of R9, R10, R11, and R12 is other than H, then at least one of R9, R10, R11, and R12 is:
(I) preferably selected from: (1) C1 to C4 alkyl, (2) xe2x80x94CON(R18)2 or (3) the cycloalkyl ring formed when R9 and R10, and/or R11 and R12, are taken together along with the carbon atom to which they are bound;
(II) most preferably selected from: (1) methyl, (2) isopropyl, (3) xe2x80x94CONH2 or (4) cyclopropyl; and
(III) more preferably selected from: (1) R9 and R10 being H, and one of R11 and R12 being selected from: alkyl (preferably, methyl or isopropyl), and the other being selected from H or alkyl (preferably, methyl); (2) R9 and R10 being H, and R11 and R12 being taken together to form a cycloalkyl ring (preferably, cyclopropyl); or (3) R11 and R12 being H, and one of R9 and R10 being xe2x80x94CONH2, and the other being H.
Preferred compounds, when at least one of R9, R10, R11, and R12 is other than H, also include compounds wherein: R9 and R10 are H, and R11 and R12 are the same or different alkyl, preferably the same, wherein said alkyl is more preferably methyl.
For compounds of the invention, n is preferably 0-4, more preferably 0-2, and most preferably 0 or 1.
Preferably, each R32 and R33 are independently selected from: H, xe2x80x94OR18, aryl or arylalkyl (e.g., benzyl); most preferably H, xe2x80x94OH or phenyl; and more preferably H.
Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R- and S- isomers: 
Compounds of formula 1.0 also include compounds having the 2S stereochemistry and the C-11 R- or C-11S- stereochemistry.
Compounds of this invention include: 
Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that the compounds have the 2S stereochemistry.
Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl.
Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl and the compounds have the 2S stereochemistry.
Preferred compounds of formula 1.0 include compounds of the formula: 
(i.e., wherein R14 is the carbamate group 5.0) wherein all substituents are as above defined.
A preferred compound of formula 25.0 is: 
with formula 27.0: 
being most preferred (wherein all substituents are as defined above).
Compounds of formula 25.0 include: 
wherein all substituents are as defined above.
Preferred compounds of formulas 28.0 and 29.0 are those wherein the R1 to R4 substituents are selected to produce trihalo, dihalo and monohalo substituted compounds, as described above.
Compounds of formula 29.0 are preferred. Most preferred are compounds of formula 29.0 wherein R8 is selected from: benzyl, 4-fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl; R20 is cyclohexyl, i-propyl or t-butyl (more preferred is cyclohexyl), R1 is Br or H, R3 is Cl, and R4 is H. More preferred are compounds of formula 29.0 wherein R8 is benzyl, R20 is cyclohexyl. i-propyl or t-butyl (even more preferred cyclohexyl), R1 is H, R3 is Cl, and R4 is H or Cl.
Preferred compounds of this invention include: 
Most preferred compounds include the compounds 
More preferred compounds include the compounds of Examples 58, 199, 225, 226, 229, 232 and 326. Compounds of Examples 58, 199, 225, 229 and 326 are even more preferred. The compound of Example 225 is even still more preferred. Preferably the compound of Examples 225, 229 and 326 are administered orally.
This invention is also directed to the compounds of Examples 26, 30, 32, 41, 42, 43, 44, 81, 105, 106, 293, and 309. The compound of Example 309 is preferred.
This invention is also directed to the compounds of Examples 31, 34, 35, 36, 37, 38, 39, 40, 67, 68, 69, 70, 73, 75, 263, 282, 283, 284, 287, and 289. The compounds of Examples 67, 68, 69, and 70 are preferred.
This invention is also directed to the compounds of Examples 27, 28, 29, 71, 72, 74, 76, 98, 101, 103, 104, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 285, 286, 286A, 290, 291, 292, 294, 295, 296, 297, 299, 300, 301, 302, and 303. Compounds of Examples 101, 103, 71, 72 Step B, 72 Step C and 259 are preferred This invention is also directed to compounds of Examples 33, 279, 280, and 281.
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
Compounds of the invention may be prepared according to the procedures described in WO95/10516 published Apr. 20, 1995, WO96/31478 published Oct. 10, 1996, WO97/23478 published Jul. 3, 1997, U.S. Pat. No. 5,719,148 issued Feb. 17, 1998, and copending application Ser. No. 09/094,687 filed Jun. 15, 1998 (see also WO98/57960 published Dec. 23, 1998); the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.
Compounds of the invention can be prepared according to the reaction schemes described below. 
In Scheme 1, R11 and R12 are preferably methyl when H is bound to the amide nitrogen (i.e., when R8 in formula 1.0 is H), e.g., 41.0, and are preferably H when the amide nitrogen is substituted (i.e., R8 in formula 1.0 is other than H), e.g., 41.1. Those skilled in the art will appreciate that other acylating agents can be used in place of cyclohexyl isocyanate to obtain compounds having different groups bound to the carbonyl group that is bound to the piperazine nitrogen. Those skilled in the art will also appreciate that other esters can be used in place of compound 31.0 to obtain compounds having different carbon chains between the imidazole ring and the C(O)NH-group.
Compounds of 41.0 can be prepared beginning with the conjugate addition of imidazole (2-, 4-, and/or 5-substituted) to an appropriately substituted acrylate 31.0 in EtOH at reflux or neat at 90xc2x0 C. Standard LAH reduction of the ester 32.0 gives the alcohol 33.0 which can be converted to the phthalimide 35.0 via the Mitsunobu reaction. Removal of the phthalimido group with hydrazine in EtOH at reflux gives amine 36.0. This amine readily opens the piperazine anhydride 37.0 with the evolution of CO2 and subsequent reaction with isocyanates gives the one pot conversion to urea 38.0. Removal of the BOC-group with 50% TFA at room temperature gives the salt 39.0, which can be readily coupled to the tricyclic chloride 40.0 to give the desired product 41.0.
In Scheme 1, and the Schemes that follow, Y represents C, N or N+Oxe2x88x92 such that there can only be 0-2 Y substituents that are independently selected from N or N+Oxe2x88x92. RA represents the optional substituents in the imidazole ring that are defined for imidazole ring 4.0 above. RB represents the optional substituents defined above for the aryl or heteroaryl groups for R8.
For example, following Reaction Scheme 1, wherein R11 and R12 are methyl, and using compound 42.0 (see Preparative Example 40 in WO95/10516 published Apr. 20, 1995) can be obtained. 
The synthesis of the intermediate amine 51.0 begins with the alkylation of the sodium salt of imidazole (or substituted imidazole) 44.0 with 45.0 at 90xc2x0 C. Standard LAH reduction of the ester 46.0 gives the alcohol 47.0. Tosylation of 47.0 and displacement of tosylate with potassium phthalimide 49.0 in DMF at 90xc2x0 C. gives the phthalimido derivative 50.0 which can be readily converted to the amine 51.0 with hydrazine in refluxing EtOH. Compounds wherein R8xe2x89xa0H can be prepared as described in Scheme 1.
Similar to the procedure set forth in Scheme 1 for 36.0 and 36.1, 51.0 and 51.1 in Scheme 2 are reacted to form compounds of formula 1.0. In Scheme 2, R11 and R12 are preferably methyl when H is bound to the amide nitrogen (i.e., when R8 in formula 1.0 is H), and are preferably H when the amide nitrogen is substituted (i.e., R8 in formula 1.0 is other than H). 
Compound (xc2x1) 52.0 is resolved following procedures similar to those disclosed in WO97/23478 (published Jul, 3. 1997).
The reagents used in Reaction Scheme 3 are: Reaction Step a: Isatoic anhydride/methylene chloride; Reaction Step b: sodium nitrite/hydrochloric acid/methanol/cuprous chloride; Reaction Step c: (i) aq. hydrochloric acid/methanol/reflux (ii) sodium hydroxide/sodium cyanide; Reaction Step d: conc. hydrochloric acid/reflux.; and Reaction Step e: di-tert.butyldicarbonate/-sodium hydroxide/tetrahydrofuran. 
In Scheme 5, R30 represents: 
In Scheme 6, the procedure set forth in Scheme 4 is followed, but using 
instead of 
to obtain the corresponding urea (xe2x80x94C(O)NHR20), amide (xe2x80x94C(O)CH2R20 or xe2x80x94C(O)R20), sulfonamide (xe2x80x94SO2R20) or carbamate (xe2x80x94C(O)OR20) products, wherein n is 0, can be prepared. Similarly, using 
(obtained from XI following the procedures in Scheme 4), instead of 
in Scheme 4 and 5 produces the corresponding ureas, amides, sulfonamides and carbamates wherein n is 0.
Those skilled in the art will appreciate that in Schemes 1, 2 and 4-6, other aldehydes can be used in place of 
to obtain the other substituents for R8 in formula 1.0.
Those skilled in the art will also appreciate that using 
instead of 
in Schemes 4 and 5, and using 
instead of 
in Scheme 6 will provide the corresponding compounds wherein the imidazole is bound to the alkyl chain by a ring carbon.
Reaction Scheme 7 (R9 and R10 Are Other Than H) 
In Scheme 7, the alcohol 33.0 can be oxidized under standard conditions to give the aldehyde. Addition of the corresponding Grignard of R9 gives the alcohol which can be carried on to amine as in Scheme 1 or subject to reoxidation to the ketone followed by Grignard addition of R10. In the case where R9xe2x95x90R10, the ester 32.0 (Scheme 1) can be used as the electrophile with 2 equivalents of the appropriate Grignard reagent being added.
Reaction Scheme 8 (R9 and R10 Are Other Than H, C-Linked Imidazole) 
In Scheme 8, the nitrile may be reduced with DIBAL-H to the aldehyde. Similar to the procedure in Scheme 7, the aldehyde can then be treated with the appropriate Grignard reagent to give the alcohol. There can be an additional round of oxidation and Grignard addition to give the R9, R10 disubstituted derivatives with either R9=R10 or R9xc2x7R10. The resulting alcohol may be converted to the amine by the methodology shown in either Schemes 1 or 2.
Compounds useful in this invention are exemplified by the following examples, which examples should not be construed as limiting the scope of the disclosure.